How are vaccine safety questions answered and by whom?
The safety of vaccines is evaluated consistently from clinical trials all the way to post-authorization/post-licensure studies. In clinical trials, vaccines are usually assessed for local and systemic events. Vaccines are said to be reactogenic or have high reactogenicity if they elicit substantial inflammation subsequent to immunization. Reactogenic events can include local outcomes such as injection site pain and redness/swelling at the injection site, as well as systemic outcomes including myalgia, arthralgia, fever and headache (Hervé, September 2019).
Sometimes, rare events may occur after vaccination that are too rare to be identified within clinical trials. These could include outcomes such as Guillain-Barré syndrome, ischemic stroke or myocarditis. Because background rates of these outcomes are very low, the only way to appropriately assess differences in risks of these outcomes is to measure relative risks in large populations. Therefore, vaccines continue to be assessed for safety in much larger populations (millions or tens of millions of people) after they are authorized and/or licensed for use. There are several infrastructures in place to investigate vaccine safety outcomes after vaccine authorization or licensure in the United States. These include the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD). Additional safety investigations and considerations are performed by FDA’s BEST system and by using information from the Centers for Medicare & Medicaid Services. Each of these systems plays a distinct and important role in COVID-19 vaccine safety investigations in the U.S.
Vaccine safety infrastructure in the U.S.
VAERS is an open database that collects reports of adverse events following vaccination. Health care providers are required to report certain COVID-19 vaccine safety outcomes to VAERS, but anyone can report events to VAERS, including care providers, child care professionals and individual patients/laypeople. VAERS is not structured to formally investigate causal relationships between vaccines and potential safety outcomes (Dusto, May 2022). Instead, it is an early warning system used to generate hypotheses about vaccine safety that can then be investigated using more robust methods.
VSD is composed of several large managed-care organizations in the U.S. Information from the electronic health records of individuals at these managed-care organizations is combined to investigate formally hypothesized relationships between vaccines and specific safety outcomes. These hypotheses may come from VAERS, v-safe or medical literature. VSD has been in existence since 1990 and currently includes electronic health data for approximately 3% of the U.S. population.
Until May 2023, CDC’s v-safe smartphone-based reporting system collected user-input data for COVID-19 vaccines specifically. In addition to common and usually nonserious adverse effects such as injection site pain, fatigue and headache, some more serious safety signals have been identified in relation to COVID-19 vaccination thanks to a combination of the vaccine safety infrastructures described above.
History of COVID-19 vaccine safety investigations in VAERS and VSD
VAERS, v-safe and VSD have all been continuously monitoring the safety of COVID-19 vaccines since they were originally rolled out. Specific U.S.-based safety investigations have included (not an exhaustive list):
Overall assessments
- An early assessment of mRNA vaccine safety during the first 6 months of the U.S. vaccination program (December 2020 – June 2021, involving 7.9 million v-safe participants)
- An early assessment of vaccine reactogenicity in the 2 weeks following mRNA vaccination (December 2020 – March 2021, including 4.7 million v-safe registrants)
- A broad assessment of COVID-19 vaccine safety, 2020 -2021 (4.1 million Pfizer-BioNTech vaccines, 2.6 Moderna vaccinees and 0.4 million Janssen vaccinees included)
- Identifying the risk of rare severe allergic reactions among Moderna-vaccinated people, December 2020 – January 2021 (4.0 million doses of Moderna)
- Safety monitoring of Janssen/J&J vaccine up to April 2021 (assessing VAERS reports during a time when nearly 8 million doses of Janssen had been administered)
- Assessing the risk of non-COVID-19 mortality among vaccinated vs. unvaccinated people, December 2020 – July 2021 (6,974,817 unique individuals, vaccinated and unvaccinated, were included, of whom 3.3 million received at least one dose of Pfizer-BioNTech, 2.4 million received at least 1 dose of Moderna and 331,282 people received one dose of Janssen)
- Safety of COVID-19 vaccination in adults with prior COVID-19 infection, December 2020 – May 2021 (study in 6.5 million v-safe participants)
- Assessing the risk of 23 rare and serious health outcomes among all individuals receiving mRNA COVID-19 vaccines, December 2020 – June 2021 (data from 6.2 million individuals who received 11.8 million doses of mRNA vaccines)
- Measuring the incidence of Guillain-Barré syndrome after COVID-19 vaccination, December 2020 – November 2021 (15,120,073 COVID-19 vaccine doses given to 7,894,989 individuals)
- An investigation of menstrual irregularities and vaginal bleeding after COVID-19 vaccination reported to v-safe from December 2020 through January 2022 (63,815 respondents)
- Measuring the risk of myocarditis and pericarditis following mRNA COVID-19 vaccination, December 2020 – January 2022 (2.9 million doses of Pfizer-BioNTech and 1.8 million doses of Moderna assessed)
- Assessing the risk of outcomes after Janssen vaccine in adults, February 2021 – February 2022 (17,018,042 doses assessed)
- Assessment of bivalent mRNA booster safety among individuals ≥ 12 years old, August 2022 – October 2022 (involving 211,959 v-safe registrants)
- Assessment of reactogenic events after simultaneous administration of COVID-19 mRNA vaccine and influenza vaccine in individuals ≥ 12 years of age, September 2021 – May 2022 (92,023 simultaneous administration events in individuals registered with v-safe)
Assessments in children
- COVID-19 vaccine safety in children 5-11 years old (November 2021 – December 2021, investigating VAERS reports during a time when 8.7 million doses of Pfizer-BioNTech were administered to children 5-11 years old)
- An assessment of reactions following Pfizer-BioNTech vaccination among children 5-11 years old, November 2021 – February 2022 (including 7,077 children who received Pfizer-BioNTech vaccine)
- COVID-19 booster safety among individuals 12-17 years of age, December 2021 – February 2022 (monitoring reports to VAERS during a time when 2.8 million U.S. adolescents received Pfizer-BioNTech)
- COVID-19 vaccine safety in adolescents 12-17 years of age, December 2020 – July 2021 (monitoring VAERS reports during a time when 8.9 million adolescents received boosters and including approximately 129,000 v-safe registrations)
- COVID-19 vaccine safety in adolescents up to May 2022 (172,032 adolescents enrolled in v-safe)
- Assessing safety of mRNA vaccines among young children, June 2022 – March 2023 (550,000 children under 5 years of age)
- Safety monitoring of mRNA COVID-19 vaccine third doses among children under 5 years of age, June 2022 – May 2023 (495,576 children received Pfizer-BioNTech; 63,919 received Moderna)
- Safety of COVID-19 vaccination in children 5-11 years old (48,795 v-safe registrants plus 726,820 doses identified in VSD)
Booster-related
- Assessment of COVID-19 booster safety in adults, September 2021 – February 2022 (721,562 v-safe registrants)
- A broad assessment of COVID-19 booster vaccine safety, including boosters received through April 2022 (2.4 million Pfizer-BioNTech vaccinees and 1.8 million Moderna vaccinees)
- Assessment of second booster dose safety among adults ≥ 50 years old, Mary 2022 – July 2022 (286,380 v-safe participants)
- Booster vaccine safety among children 5-11 years of age, May 2022 – July 2022 (including 3,249 Pfizer-BioNTech vaccines reported to v-safe)
- Assessment of safety of bivalent mRNA boosters among children 5-11 years of age, October 2022 – January 2023 (including 861,251 children receiving Pfizer and 92,108 receiving Moderna)
Immunocompromised populations and pregnant people
- Preliminary findings for COVID-19 mRNA vaccine safety in pregnant individuals, December 2020 – February 2021 (35,691 v-safe participants)
- Risk of additional dose (third primary series dose) to immunocompromised individuals, August 2021 – September 2021 (22,191 v-safe registrants who received a third dose)
- Assessing the risk of spontaneous abortion (miscarriage) after COVID-19 vaccination in v-safe, December 2020 – July 2021 (2,456 v-safe registrants)
- Assessing the risk of spontaneous abortion (miscarriage) following COVID-19 vaccination of pregnant individuals, December 2020 – June 2021 (following 105,446 unique pregnancies where 7.8% of women received one or more Pfizer-BioNTech vaccine, 6.0% of women received 1 or more Moderna vaccine, and 0.5% received Janssen)
- Assessing the risk of spontaneous abortion (miscarriage) following COVID-19 booster vaccination of pregnant individuals, November 2021 – June 2022 (112,718 unique pregnancies in the study and 270,853 controls)
- Safety of first mRNA vaccine boosters among individuals ≥ 12 years old with presumed immunocompromise, January 2022 – March 2022 (4,015 v-safe registrants)
How is vaccine safety information used in policy decisions?
At CDC’s Advisory Committee on Immunization Practices meetings, information from published and as-yet-unpublished vaccine safety research is shared and discussed. This information is first discussed, analyzed and synthesized in vaccine-specific workgroups, including the Vaccine Safety Technical Workgroup. After workgroup discussions, the findings of the workgroup are presented more broadly in public discussions with all ACIP members. Additional presentations from vaccine safety research may also occur in broader, public ACIP meetings. The findings of safety studies play an important role in ACIP recommendations for vaccine policy. For example, after updated safety information regarding rare outcomes following the Janssen/Johnson & Johnson vaccine in December 2021, ACIP reviewed the evidence and issued a recommendation that mRNA vaccines were preferred over the Janssen/Johnson & Johnson vaccine.
What is the current status of COVID-19 vaccine safety research?
COVID-19 vaccine safety has been, and continues to be, very thoroughly and consistently investigated throughout the course of the pandemic. For each outcome that has been investigated and analyzed, the findings have been that the benefits of COVID-19 vaccination outweigh any potential risks caused by vaccines. Many outcomes are easily identified using International Classification of Diseases codes found in electronic health records. Some outcomes require further investigation, including manual review of medical records by trained research staff.
Still other outcomes may be extraordinarily challenging to identify using large-scale data. For example, the possibility of autonomic dysfunction after COVID-19 vaccination has recently been raised (Vogel, July 2023). The investigation of dysautonomia and similar syndromes, including postural orthostatic tachycardia syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and complex regional pain syndrome, is challenging because these syndromes often take a long time to develop and a long time to diagnose.
There are additional key concerns surrounding substantial potential inequity in how these syndromes may be diagnosed, according to race, sex and other social determinants of health. Additionally, for some of these syndromes, there are no dedicated ICD codes, meaning that algorithms, manual chart review or direct patient surveys may be required to appropriately identify the outcome. The challenging nature of these outcomes does not outweigh the importance of assessing them for vaccine safety considerations. For such outcomes, additional novel methodology for vaccine safety investigations is being considered and being used, including natural language processing, machine learning methods and artificial intelligence.